Phosphate derivatives are key metabolic intermediates in virtually all aspects of cellular metabolism. In addition many antineoplastic and antiviral drugs require intracellular phosphorylation in order to be biologically active. However, the pharmacological utility of phosphate derivatives is severely hampered by the inability of negatively charged phosphate derivatives to permeate into cells and through the blood brain barrier.
Studies have been published describing lipophilic, negatively charged phosphate derivatives of Arabino-furano-sylcytosine (ARA-C). E. K. Ryu et al., J. Medicinal Chem., 25:1322 (1982); C. I. Hong et al., J. Medicinal Chem., 28:171 (1985); A. Rosowsky et al., J. Medicinal Chem., 25:171 (1982). However, these prodrug derivatives form liposomal aggregates in water which lead to unacceptable pharmacological properties. MacCross et al., Biochemical and Biophysical Research Comm., 116:368 (1983). Neutrally charged phosphorodiamidates have been suggested as phosphate prodrugs. M. E. Phelps et al., J. Medicinal Chem., 23:1229 (1980). However, this method is ineffective. Chawla, R. R. et al., J. Medicinal Chemistry, 27:1733 (1984). Similarly, cyclic phosphoramidate derivatives have been tested as potential prodrugs without success. Kumar, A. et al., J. Medicinal Chemistry, 33:2368 (1990). Neutrally charged phosphate prodrugs with good leaving groups have been described. Chawla et al., ibid., Farrow, S. N. et al., J. Medicinal Chemistry, 33:1400 (1990). However, neutrally charged phosphate esters which have a good leaving group on the phosphorus are in general extremely toxic inhibitors of acetylcholinesterase. Holmstedt, B., Pharmacological Reviews, 11:567 (1959). Phosphotriester derivatives which lack acetylcholinesterase activity are in general not catabolized by cellular enzymes to phosphodiesters. Benzylic 3'5' cyclic monophosphate triesters have been employed as prodrugs for cyclic nucleotide monophosphate derivatives with variable success. Engels, J. et al., J. Medicinal Chemistry, 20:907 (1977); Beres, J. et al., J. Medicinal Chemistry, 29:494 (1986); Beres, J. et al., J. Medicinal Chemistry, 29:1243 (1986). Primary benzylic phosphate esters are alkylating agents and potentially toxic. In addition the slow rate of hydrolysis of benzyl phosphate diesters to phosphate monoesters precludes the use of dibenzyl phosphotriesters as prodrugs. Acyloxymethyl phosphate esters have been described as potential prodrugs. Farquhar, D. et al., J. Pharmaceutical Sciences, 72:325 (1983); Farquhar, D. et al., Biorganic Chemistry, 12:118 (1984). Acyloxyalkyl bis phosphonate esters have been tested as prodrugs for a phosphonate compound and were found to be ineffective. Iyer, R. et al., Tetrahedron Let., 30:7141 (1989). Bis (pivaloyloxy-methyl) prodrugs of PMEA enhance intracellular PMEA delivery in vitro and have enhanced antiviral activity in vitro. However, the utility of these compounds is limited by chemical instability. Srinivas, R. V. et al., Antimicrob Agents Chemother., 37:2247 (1993); Starrett, J. E. et al., Antiviral Res, 19:267 (1993); Starrett, J. E. et al., J. Med. Chem., 37:1857 (1994). The bis (pivaloyloxymethyl) prodrug of PMEA is undetectable in the blood of animals following oral administration. Only PMEA is detectable. The bis (pivaloyloxymethyl) prodrug of PMEA increases the oral absorption of PMEA to about 27% by acting at the level of the gastrointestinal tract. However, it does not enhance the delivery of PMEA at the tissue level. Cundy, K. C. et al., Pharmaceutical Res., 11:839 (1994). Acyloxyalkyl prodrugs of PMEA also do not display significantly enhanced activity against the AIDS virus. Starrett, J. E. et al., Antiviral Research, 19:267 (1992). Bis phosphoesters of 2,2'dithioethanol are highly effective prodrugs in vitro. Puech, F. et al., Antiviral Research, 22:155 (1993). However, the metabolism of these prodrugs generates 2 mole equivalents of ethylene sulfide, which is extremely toxic. Lactyl, glycolyl, and alaninyl phosphates have also been tried as prodrugs with variable success. McGuigan, C. et al., Antiviral Research, 17:197 (1992).